1. Field of the Invention
The present invention relates to a method of treating ovarian, tubal and peritoneal cancer, especially for applying a pharmaceutical composition comprising a copper chelator, a platinum-based chemotherapeutic agent and an anthracycline to a subject in need thereof. The copper chelator lowers intracellular copper ion levels and promoting activation of transcription factor Sp1 and human copper transporter 1 (hCTR1), resulting in an increased uptake of the platinum-based chemotherapeutic agent as well as the anthracycline, and reduced proliferation of cancer cells.
2. Description of Related Art
Growing evidence implicates tubal cancer, ovarian cancer, and so-called primary peritoneal carcinomas as having a common origin, pathogenesis, and behavior (Annu Rev Pathol. 2014; 9:27-45). Hence, ovarian cancer cell lines are usually used for in-vitro and animal studies for these three cancers. Regarding the treatment, the NCCN Guidelines discuss fallopian tube cancer and primary peritoneal cancer that are managed in a similar manner to epithelial ovarian cancer. In the clinic, these cancers are treated with the same chemotherapeutic agents even when they recur after primary therapy. Additionally, clinical trials for ovarian cancer are commonly designed to enroll patients with these three cancers.
Usually, tubal cancer, ovarian cancer, and primary peritoneal carcinomas are found at a late stage. According to NCCN Clinical Practice Guidelines in Oncology, these patients are generally administered with platinum-based chemotherapeutic compounds after a debulking operation. However, cancer cells treated with platinum-based chemotherapeutic drugs frequently develop chemoresistance and result in treatment failure. Hence, an increased dosage of drugs or different strategies for improving the treatment against chemoresistant cancer cells is necessary.
Currently a variety of treatment strategies are developed, e.g. liposomal doxorubicin, hycamtin and the like. However, the use of these second-line drugs may not enhance the treatment efficacy. As a result, the mortality rate remains high due to cancer recurrence. Additionally, US Patent Pub. No. 2006/0013819, have disclosed a method for treating platinum-resistant, ovarian cancer, primary peritoneal carcinoma or fallopian tube carcinoma with the combination of a HER2 antibody that effectively inhibits HER dimerization as well as gemcitabine. However, the therapeutic effect of abovementioned method is still limited.
The present inventors found that copper chelator can lower intracellular copper ion levels and increase Sp1 and hCTR1 activation, allowing chemotherapeutic agents to be transported into ovarian cancer cells in basic research. Furthermore, they also observed significantly treatment effect in animal experiments.
Nowadays there are numerous chemotherapeutic agents on the market. Therefore, how to develop a pharmaceutical composition comprising copper chelating agents in combination with chemotherapeutic agents for overcoming chemoresistance of these three cancers is still an important goal in cancer therapy.